Parts of these results were presented in a late-breaking abstract at the 112th ASCPT meeting, Denver, 2–5 March 2011 (Poster No.LBIII-2).
Oral bioavailability of dabigatran etexilate (Pradaxa®) after co-medication with verapamil in healthy subjects
Version of Record online: 15 MAR 2013
© 2012 Boehringer Ingelheim Pharma GmbH & Co. KG.. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 4, pages 1053–1062, April 2013
How to Cite
Härtter, S., Sennewald, R., Nehmiz, G. and Reilly, P. (2013), Oral bioavailability of dabigatran etexilate (Pradaxa®) after co-medication with verapamil in healthy subjects. British Journal of Clinical Pharmacology, 75: 1053–1062. doi: 10.1111/j.1365-2125.2012.04453.x
- Issue online: 15 MAR 2013
- Version of Record online: 15 MAR 2013
- Accepted manuscript online: 5 SEP 2012 04:21AM EST
- Manuscript Accepted: 28 AUG 2012
- Manuscript Received: 14 OCT 2011
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
- Boehringer Ingelheim
- dabigatran etexilate;
- drug interaction;
- Pradaxa®, verapamil
To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE).
In this two part multiple crossover trial in 40 healthy subjects, DE 150 mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time.
The greatest effect was observed with single dose verapamil 120 mg immediate release given 1 h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,∞)] and maximum analyte concentration in the plasma (Cmax) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax, respectively, when DE was administered with verapamil 240 mg extended release. After multiple verapamil dosing, DE AUC(0,∞) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,∞) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentration–effect relationship was generally not affected by the co-administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings.
Verapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2 h prior to verapamil.